Neurotoxicity mechanism of aconitine in HT22 cells studied by microfluidic chip-mass spectrometry

Aconitine,a common and main toxic component of Aconitum,is toxic to the central nervous system.However,the mechanism of aconitine neurotoxicity is not yet clear.In this work,we had the hypothesis that excitatory amino acids can trigger excitotoxicity as a pointcut to explore the mechanism of neurotoxicity induced by aconitine.HT22 cells were simulated by aconitine and the changes of target cell metabolites were real-time online investigated based on a microfluidic chip-mass spectrometry system.Meanwhile,to confirm the metabolic mechanism of aconitine toxicity on HT22 cells,the levels of lactate dehydrogenase,intracellular Ca^(2+),reactive oxygen species,glutathione and superoxide dismutase,and ratio of Bax/Bcl-2 protein were detected by molecular biotechnology.Integration of the detected results revealed that neurotoxicity induced by aconitine was associated with the process of excitotoxicity caused by glutamic acid and aspartic acid,which was followed by the accumulation of lactic acid and reduction of glucose.The surge of extracellular glutamic acid could further lead to a series of cascade reactions including intracellular Ca^(2+)overload and oxidative stress,and eventually result in cell apoptosis.In general,we illustrated a new mechanism of aconitine neurotoxicity and presented a novel analysis strategy that real-time online monitoring of cell metabolites can provide a new approach to mechanism analysis.

Neurotoxic mechanism of 1-methyl-4-phenyl-1,2,3,6-tetradropyridine

BACKGROUND ： To summarize the metabolic pathway of 1-methyl-4-phenyl-1,2,3,6-tetradropyridine （MPTP） and its mechanism in inducing Parkinson disease. DATA SOURCES： A computer-based online search of Medline database was undertaken to identify articles about the metabolic pathway of MPTP and its mechanism in inducing Parkinson disease published in English between January 1996 and August 2004, the keywords were ＂MPTP, Parkinson disease＂. Meanwhile, Chinese relevant articles published between January 2000 and August 2004 were searched in Wanfang database with the keywords of ＂MPTP, Parkinson disease＂. STUDY SELECTION： More than 300 relevant literatures were retrieved, and the full-texts were further searched, those about the establishment of animal models, molecular mechanism of MPTP neurotoxicity and the metabolism were selected, and the obviously repetitive ones, case report and reviews were excluded, finally 18 of them were selected for summarization. DATA EXTRACTION： The 18 literatures were categorized according to MPTP induced animal models of Parkinson disease, mechanism of MPTP in inducing apoptosis in models of Parkinson disease, role of dopamine in the neurotoxic mechanism of MPTP, the role of reactive oxygen species and nitric oxide in the neurotoxicity of MPTP. DATA SYNTHESIS： Animal models of Parkinson disease induced by MPTP can not only produce the clinical characters of Parkinson disease, also duplicate the main biochemical and pathological changes of Parkinson disease. The metabolic pathway of MPTP and its mechanism in inducing Parkinson disease included producing free oxygen and nitric oxide, damaging mitochondrial respiratory chain, and inducing apoptosis, etc. which could all lead to the degeneration and loss of dopaminergic neurons. CONCLUSION ： Although some aspects of the models of Parkinson disease are different from that in human beings, we can still know the neurodegeneration of Parkinson disease through studying the molecular mechanism of MPTP.